Allergic disorders are caused by an allergic reaction which, as a result of an antigen-antibody reaction, brings about a pathogenesis in a living organism. The mechanism of pathogenesis of allergic disorders is believed to follow the following course. When exposed to a pathogenic antigen, a living organism produces antibodies. The second attack of the same antigen causes an antigen-antibody reaction and, as a result, chemical mediators are released from the cells. These mediators damage tissues and/or the formed antigen-antibody complexes are deposited on the tissues, causing allergic disorders or autoimmune disorders. Among various pathogenic antigens are included xenogenic antigens, such as inhaled allergen, food allergen, drugs, contact allergen, and allogenic or autolous antigens which originate from autologus components of the tissues or organs denatured for some reason and thereby behaving as foreign substances.
So-called allergic disorders caused by enogenic antigens, such as bronchial asthma, food allergy or urticaria, are classified into four types according to their symptoms or causes. That is, they are classified into Type I allergies (anaphylactic-type) resulting from tissue-depositing antibodies and characterized by increased capillary permeability and smooth muscle contraction, Type II allergies (cytotoxic-type) resulting in the presence of complements and characterized by cell damage, Type III allergies (Arthus-type) resulting from the deposition of antigen-body complexes on vacular walls and subsequent participation of complements and polymorphonuclear leucocytes and characterized by inflammatory reactions, and Type IV allergies resulting from cell-mediated immunity and characterized by the appearance of delayed hypersensitivitiy such as Tuberculin reaction. Among the allergic reactions, Types I, III and IV allergies participate in, for example, bronchial asthma and each of these reactions is considered independently or in combination to cause asthma attack. The pathogenic mechanism of these allergic disorders can be considered to act as follows.
An antigen which invades a living organism is treated by macrophages, and the immunological information on the antigen is transmitted to the T cell-B cell system. The B cells which have received the information produce immunoglobulin (Ig E antibody is mainly produced in Type I allergies and Ig G antibody is mainly produced in Type II and Type III allergies) and the Ig E antibody binds to the basophils in the circulation or to the most cells in the tissues, thereby establishing the state of sensitization. The same antigens which invade the sensitized organism bind to cell-bound antibodies, allowing them to release chemical mediators such as histamine and slow-reacting substances of anaphylaxis (SRS-A). The released chemical mediators induce allergic symptoms such as erythema, edema or increase of glandular secretion caused by contraction of smooth muscles and increase of capillary permeability. On the other hand, Ig G antibody binds to polymorphonuclear leucocytes to achieve sensitization and the subsequent secretion of SRS-A as a chemical mediator is also suspected.
Anti-allergic agents may achieve therapeutic purpose by suppressing any step in these processes.
Conventionally, xanthine derivatives, .beta.-adrenergic stimulants (.beta.-stimulants) or corticosteroids have been used for the treatment of asthma. However, these drugs are frequently observed to show undesirable adverse reactions. For instance, palpitation, tachycardia, etc., are reported with respect to xanthine derivatives and .beta.-stimulants. Furthermore, corticosteroids cause adverse reactions such as peptic ulcers and complications of bacterial infection. Moreover, anti-histamine agents may cause difficulty in the expectoration of tracheal secretion, rather than being effective against asthma attack, so that they may sometimes worsen the clinical condition of asthma.
Immune complex diseases or autoimmune disorders in which the pathogenic antibody is an auto-antigen, typified by rheumatoid arthritis, systemic lupus erythematosus (SLE) and lupus nephritis, as implied by the names, are disorders resulting from complexes of antigens and antibodies, namely, immune complexes. Although the pathogenetic mechanism of immune complex diseases is complicated and has not been resolved in many respects, it is generally believed to follow the following course. When the tissues are damaged by bacterial or viral infections, antibodies are produced against the freshly produced autoantigens or virally-infected cells and they react with the corresponding antigens to form immune complexes. Since these immune complexes activate the complement system and platelets, vasoactive substances such as histamine and serotonin are released and the permeability of the blood vessels is increased. Then, the immune complexes in circulation penetrate into the vascular walls having increased permeability and deposit along the basement membranes. Polymorphonuclear leucocytees are gathered on the deposited sites of the immune complexes by the action of the leucocyte chemotactic factors produced by the addition of the complement upon the deposited immune complexes. The polymorphonuclear leucocytes, reacting with the immune complexes, release various tissue-damaging substances such as cathepsin D and E, collagenase, elastase and permeability factors, and these substances eventually damage the tissue. The level of complement in the serum from a patient with an immune complex disease such as SLE is generally low and aggravation of the disease conditions is closely correlated with the decrease of the complement level. This decline of complement level is considered to be due to a plentiful consumption of complement at the site of the reaction between antigens and antibodies taking place such as kidneys and blood vessels. Moreover, it is considered that the immune complexes are also related to blood coagulation systems and they are believed to lead to more serious conditions through diverse mechanisms such as the acceleration of fibrinoid deposition onto the damaged tissues.
For the treatment of immune complex diseases, anti-inflammatory agents and immunosuppressive agents including steroids are presently used for suppressing the hypersensitized immune system and for reducing local inflammations and pains, or anticoagulants and antiplatelet agents are used for improving abnormalities of the coagulation-fibrinolysis system in the blood vessels. However, because these drugs show eak effectiveness and are associated with strong adverse reactions, it has been strongly desired to develop drugs which are safe and highly effective in the treatment of the diseases.
Furthermore, many drugs have been developed for the treatment of malignant tumors. These anti-tumor drugs are roughly classified into the following two types. The first type includes so-called cytotoxins which directly suppress tumor growth. The second type includes those drugs which indirectly control the growth of tumors by recognizing them as foreign substances through the activation of immunological protective functions of the host. However, drugs belonging to the former type do not have sufficient selective toxicity to tumor cells, and are toxic against normal cells of the host as well. Accordingly, their total dosage is limited considerably. On the other hand, the latter type, i.e. immunopotentiators, show unfavorable adverse reactions less frequently as compared with the former so that they are generally safely used. However, they have an essential problem in that since a tumor in itself is originated from normal cells of a patient any may not be sufficiently recognized as a foreign substance by the immunological protective functions, some immunopotentiators do not exhibit sufficient anti-tumor effect.